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Identification of 1,3-diiminoisoindoline carbohydrazides as potential antimalarial candidates.
|Title||Identification of 1,3-diiminoisoindoline carbohydrazides as potential antimalarial candidates.|
|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Mombelli P, Witschel MC, van Zijl AW, Geist JG, Rottmann M, Freymond C, Röhl F, Kaiser M, Illarionova V, Fischer M, Siepe I, Schweizer BW, Brun R, Diederich F|
|Date Published||2012 Jan 2|
A series of inhibitors of plant enzymes of the non-mevalonate pathway from herbicide research efforts at BASF were screened for antimalarial activity in a cell-based assay. A 1,3-diiminoisoindoline carbohydrazide was found to inhibit the growth of Plasmodium falciparum with an IC(50) value <100 nM. Synthesis of a variety of derivatives allowed an improvement of the initial antimalarial activity down to IC(50) =18 nM for the most potent compound, the establishment of a structure-activity relationship, and the evaluation of the cytotoxic profile of the diiminoisoindolines. Furthermore, interesting configurational and conformational aspects for this class of compounds were studied by computational and X-ray crystal structure analysis. Some of the compounds can act as tridentate ligands, forming 2:1 ligand-iron(III) complexes, which also display antimalarial activity in the nanomolar IC(50) range, paired with low cytotoxicity.